DESCRIPTION: (Applicant's Abstract) Arteriosclerosis, the obstruction of arteries by atherosclerotic or "fatty" plaques is one of the major factors leading to coronary disease. These plaques originate principally from macrophage-derived foam cells, which store elevated concentrations of esterified cholesterol. Acyl-CoA cholesterol acyltransferase (ACAT) catalyzes the esterification of cholesterol and may play an important role in the absorption of dietary cholesterol. Therefore, an efficient ACAT inhibitor may function therapeutically as an antiatherosclerotic agent by decreasing that absorption and limiting the conversion of macrophages into cholesterol ester-saturated foam cells. The purpose of this project is to develop an effective inhibitor for ACAT based upon the structure of a phytotoxin, helminthosporol, which has shown moderate inhibitory activity. Identifying the structural features most important to activity is central to development of an inhibitor. Therefore, helminthosporol, two biogenetically-related metabolites known as prehelminthosporol and sorokinianin, and several minimized analogs will be prepared by total chemical synthesis. Synthetic access to all these targets will originate from a single generalized route, based fundamentally upon a divinylcyclopropane rearrangement of vinyl-substituted (3.1.0)-bicyclohexanones. The divinylcyclopropane precursor can easily be converted into the (3.2.1)-bicyclooctane nucleus that composes the helminthosporol natural products. A well-precedented in vitro assay that employs C-14- labeled-oleate will be used to determine the extent of ACAT inhibition in macrophages.